The heart has a limited capacity for regeneration following injury. Recent strategies to promote heart regeneration have largely focused on autologous and allogeneic cell-based therapy, where the transplanted cells have been suggested to secrete unknown paracrine factors that are envisioned to promote endogenous repair and/or mobilization of endogenous heart progenitors. Here, we discuss the importance of paracrine mechanisms in facilitating replication of endogenous epicardial progenitor cells in the adult heart and signaling their subsequent reactivation and de novo differentiation into functional cell types such as endothelial cells and cardiomyocytes. Moreover, we discuss the use of a novel modified RNA technology in delivering such therapeutic paracrine factors into myocardium following injury. These studies suggest that modified mRNA may be a valuable experimental tool for the precise in vivo identification of paracrine factors and their downstream signaling that may promote heart repair, cardiac muscle replication, and/or heart progenitor mobilization. In addition, these studies lay the foundation for a new clinically tractable technology for a cell-free approach to promote heart regeneration.